Project Summary/Abstract: The ultimate goal of the proposed research is to improve pancreatic ductal adenocarcinoma (PDAC) patient survival and population mortality. While survival for many cancers has improved over time, the survival for PDAC, which constitutes the vast majority (90%) of all cancers of the pancreas, remains poor. This is in part because the majority of PDACs are detected late in their course when surgical resection is not possible. However, even in cases with a resectable primary tumor, cure remains elusive because of early metastases, which are frequently microscopic and undetectable. Early metastasis from very small tumors is a key barrier to improving pancreatic cancer mortality. Systematic chemotherapy can treat unseen micrometastases in early PDAC and thus has the potential to improve patient outcomes when used as an adjuvant or neoadjuvant therapy in conjunction with surgical resection and radiotherapy. At present only about 20% of diagnosed PDACs are surgically resectable at the time of diagnosis; however, promising newer chemotherapy regimens, when combined with radiotherapy as neoadjuvant treatment, may enable the definitive resection of many PDACs (30%) that are now borderline resectable or locally advanced. If proven effective, these new treatment strategies potentially represent a major step toward improving PDAC survival and may bring a cure within reach for the majority of patients diagnosed with PDAC. Yet, questions remain about how best to apply neoadjuvant and adjuvant therapy regimens, which have considerable toxicities. Care must be taken in applying the results of clinical trials to a significant proportion of patients diagnosed with PDAC, who are older and less healthy (comorbidities) than trial participants. In scenarios such as these, where there are limitations to the generalizability of clinical trial data, modeling approaches can serve a complementary role. A disease simulation model of PDAC can provide a framework to synthesize and incorporate various tumor and patient factors thereby allowing for a comprehensive balancing of the potential benefits and harms of treatment plans. The research plan will build upon prior and ongoing work by our diverse team, comprised of mathematical modelers, population scientists, cancer biologists, and clinicians with experience in all aspects of PDAC management and treatment. Our plan is to develop a comprehensive PDAC treatment model that will be analyzed to provide insights to: improve overall survival of patients with early stage PDAC, enhance decision making regarding personalized treatment plans, optimize resource utilization, and prioritize and inform future research and trials. The aims of the project will be: Aim 1-Refine and validate a model of PDAC focused on treatment; Aim 2-Design personalized treatment strategies tailored to individual patient characteristics to optimize treatment of early PDAC; Aim 3-Determine the impact of the new personalized treatment strategies on population mortality.